title: Endoplasmic reticulum stress is involved in the response of human laryngeal carcinoma cells to Carboplatin but is absent in Carboplatin-resistant cells.
abstract: The major obstacle of successful tumor treatment with carboplatin (CBP) is the development of drug resistance. In the present study, we found that following treatment with CBP the amount of platinum which enters the human laryngeal carcinoma (HEp2)-derived CBP-resistant (7T) cells is reduced relative to the parental HEp2. As a consequence, the formation of reactive oxidative species (ROS) is reduced, the induction of endoplasmic reticulum (ER) stress is diminished, the amount of inter- and intrastrand cross-links is lower, and the induction of apoptosis is depressed. In HEp2 cells, ROS scavenger tempol, inhibitor of ER stress salubrinal, as well as gene silencing of ER stress marker CCAAT/enhancer-binding protein (CHOP) increases their survival and renders them as resistant to CBP as 7T cell subline but did not influence the survival of 7T cells. Our results suggest that in HEp2 cells CBP-induced ROS is a stimulus for ER stress. To the contrary, despite the ability of CBP to induce formation of ROS and activate ER stress in 7T cells, the cell death mechanism in 7T cells is independent of ROS induction and activation of ER stress. The novel signaling pathway of CBP-driven toxicity that was found in the HEp2 cell line, i.e. increased ROS formation and induction of ER stress, may be predictive for therapeutic response of epithelial cancer cells to CBP-based therapy.
authors.affiliation: Division Of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Brozovic
authors.forename: Lidija
authors.initials: L
authors.lastname: Vuković
authors.forename: Darija Stupin
authors.initials: DS
authors.lastname: Polančac
authors.forename: Istvan
authors.initials: I
authors.lastname: Arany
authors.forename: Beate
authors.initials: B
authors.lastname: Köberle
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Fiket
authors.forename: Dragomira
authors.initials: D
authors.lastname: Majhen
authors.forename: Andreja
authors.initials: A
authors.lastname: Ambriović-Ristov
authors.forename: Maja
authors.initials: M
authors.lastname: Osmak
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D026501:Blotting, Southwestern; D015153:Blotting, Western; D016190:Carboplatin / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates; D003497:Cyclic N-Oxides; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D007822:Laryngeal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D010984:Platinum / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013113:Spin Labels; D013890:Thiourea / Q000031:analogs & derivatives
chemical_list: D002934:Cinnamates; D003497:Cyclic N-Oxides; D017931:DNA Primers; D017382:Reactive Oxygen Species; D013113:Spin Labels; C496827:salubrinal; D010984:Platinum; D016190:Carboplatin; D013890:Thiourea; C001803:tempol